Topical composition for the treatment of hyperpigmented skin

ABSTRACT

The present invention relates to novel, topically applied, cosmetic/dermatological compositions for the treatment of hyperpigmentation disorders and photodamaged human skin. The subject compositions combat hyperpigmented skin. In addition, the compounds described can be used in the treatment of many other pathologies. Due to a high degree of gentleness, along with potent antioxidant and moisturizing effects, the present invention can be used safely in the treatment of many conditions, such as the prevention and/or treatment of melasma, freckles, age spots (lentigo senilis) and photodamaged skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/624,227, filed Jul. 22, 2003, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

The present invention contains a unique combination of activeingredients for topical application. Together, these compounds seem topotentiate their effects and work in a synergistic matter. In addition,the composition of the present invention is prepared in a topicaldelivery system that enhances skin penetration. The composition isparticularly useful for treating hyperpigmentation disorders such asmelasma, postinflamatory hyperpigmen-tation, irregular pigmentationsecondary to photodamage, lentigenes (age-spots) and others. Thecomposition is nonirritating to the skin and also provides improvedfacial skin feel benefits. The unique blend is also useful forconditioning, desquamating, and cleansing the skin. The formulation canbe in the form of a leave-on product and/or can be rinsed or wiped fromthe skin after use. The base uses special preservatives and antioxidantsto achieve optimal bioavailability. The unique blend is compromised ofvismia and inositol hexaphosphate (phytic acid). Additional ingredients,such as arbutin and kojic acid, may also be included in formulations ofthe present invention. The overall benefits include lighteningpigmentation, providing even skin color and tone, improvement inphotodamage and increased clarity. Added benefits include improvement inskin smoothness, radiance and moisture retention.

Cosmetic Interest in Depigmentation and Inhibition of Melanogenesis

The use of skin-lightening cosmetics varies significantly betweencultures. In western countries, for example, skin lighteners are appliedfor the prevention and/or treatment of melasma, freckles and age spots(lentigo senilis). The treatment of irregular hyperpigmentation to reachan even skin tone is, doubtless, the main indication. In Asian andAfrican nations, on the other hand, the primary use of skin lightenersis to make the skin whiter, lighter and brighter. Interestingly, while atanned look is preferred in the West, most Asian people desire lighterskin. Traditional Asian beliefs hold that white skin denotes nobilityand aristocracy. The present invention fulfills the demand of a broadrange of these different applications in all continents.

Pigmentation

Pigmentation in animals varies greatly. It is often strikinglybeautiful. In birds, most feather coloration is due to the presence ofcarotenoic pigments. In contrast, most visible pigmentation in mammalsresults from the synthesis and distribution of the pigment melanin.Chemically, melanins are heterogeneous biopolymers produced byspecialized dendritic cells, the melanocytes, which are locatedprimarily in the skin, hair bulbs and eyes. The process by which melaninis formed is known as melanogenesis.

Visible pigmentation in mammals results from the synthesis anddistribution of melanin in the skin, hair bulbs and eyes. Tanning, acommon and often desired phenomenon in many areas of the world, issimply the result of enhanced melanin production by the skin.

Melanin, The Skin Pigment

Melanin production occurs in the skin within specialized cells known asmelanocytes. These cells originate from the neural crest and, duringembryogenesis, migrate to various sites throughout the body, includingthe skin. There they become associated either with the hair follicles orthe basal layer of the epidermis.

Epidermal melanocytes are thin, elongated dendritic cells with specificorganelles, the melanosomes, which contain all components required formelanin production. The melanocytes, which extend and branch amongneighboring epidermal cells, facilitate the transfer of melanosomes. Themelanosomes are passed to keratinocytes in skin and to the hair shaft inhair bulbs, where the final distribution patterns of the pigment aredetermined. This distribution plays an important role in determiningcolor and causes the great variety of colors that occur in the skin,hair, and eyes of humans. In this way, melanin is distributed into thesuprabasal regions of the epidermis, where it protects the germinativecells of the basal layer from ultraviolet radiation.

In the human epidermis, each melanocyte is normally associated withapproximately thirty-six (36) keratinocytes, together they constitutethe epidermal melanin unit. Although melanocyte density varies quiteconsiderably in different regions of the human skin, the total number isrelatively constant, even in different racial groups. The averagedensity is between 1,000 and 2,000 melanocytes/cm^(z) skin.

Melanin plays a crucial role in the absorption of free radicalsgenerated within the cytoplasm and in shielding the host from varioustypes of ionizing radiation, including ultraviolet

(UV) light. Thus, melanin protects the skin against sunburn, actinicdamage and cancer. Moreover, melanin can act as a thermoregulator byabsorbing different forms of energy and dissipating them as heat.Melanins are comprised of two basic types: eumelanins, which are brownor black, and phaeomelanins, which are red or yellow. In mammals,mixtures of both types are typically found. Interestingly, phaeomelaninhas the capacity to produce free radicals in response to UV radiation.Since free radicals can inflict cell injury, phaeomelanin may actuallycontribute and intensify UV-induced skin damage, rather than protect theskin.

Melanogenesis Overview (FIG. 1)

The initial compound for the production of melanin, both the brown-blackeumelanin and the yellow-red pheomelanin, is the amino acid tyrosine.The quantity of melanin synthesized is thus proportional to the amountof tyrosine activity present in the cell. Melanin synthesis starts withthe hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (L-DOPA)(see FIG. 1). This hydroxylation is the rate-limiting step in themelanogenesis pathway and is catalyzed by the key regulatory enzyme:tyrosinase. In humans, evidence indicates that human skin color can becorrelated with tyrosinase activity.

Tyrosinase is the rate-limiting, essential enzyme in the biosynthesis ofthe skin pigment melanin. As such it catalyzes three different reactionsin the biosynthetic pathway of melanin:

-   -   The hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine        (DOPA);    -   The oxidation of DOPA to DOPA-quinone;    -   The oxidation of 5,6-dihydroxyindole (DHI) to indole quinone.

Tyrosinase is a multi-functional, glycosilated, copper-containingoxidase with a molecular weight of approximately 60 to 70 KDa. Inmammals, it is exclusively found in melanocytes. It is therefore a goodmarker for melanocytes. Tyrosinase is encoded by a gene at the c-locusthat maps the chromosone 11q-14-q21 in humans and chromosone 7 in mice.

Tyrosinase is expressed specifically in pigment-producing cells.Expression of tyrosinase is regulated by cyclic AMP (cAMP). Tyrosinaseis formed within the Golgi apparatus of the melanocyte by melanosomalribosomes, tyrosinase glycosilation occurs in the endoplasmic reticulumin route to the TNGN (Trans-Golgi Network) and is transferred to themelanosome in its first stage of development (Stage I). Tyrosinase andadditional proteins are assembled in Stage II melanosomes.

The molecular basis of Oculocutaneous Albinism (OCA) results frommutations in the genes that encode tyrosinase. In OCA type 1A, mutationsin both copies of the tyrosinase-encoding gene lead to complete loss ofenzyme activity, no melanin is found in the hair, skin or eyes, alsoknown as albinism.

Recent studies have shown that mammalian melanogenesis is not regulatedsolely by tyrosinase at the enzymatic level and additional melanogenicfactors have been identified, which can modulate pigmentation in eithera positive or negative way. They have been called Melanogenesis-RelatedProteins (MRPs) and are structural proteins involved in the formation ofmelanosomes together with the enzymes involved in the transformation ofL-tyrosine to melanin: tyrosine in addition to tyrosinase relatedprotein-1 (“TRP-1”), tyrosinase related protein-2 (“TRP-2”), gp100 andPMEL 17, MART-1/Melan-A, P-protein MITF and MSH receptor.

The rate limiting steps in melanogenesis are the hydroxylation oftyrosine in the initial chemical reaction (conversation of tyrosine toDOPA), and the oxidation of DOPA by DOPA oxidase/tyrosinase (see FIG. 1)in the second reaction. In the last thirty (30) years, it has beendemonstrated that there are additional control points in the melaninbiosynthetic pathway. An example is the reaction that occurs whenDOPAchrome is converted to 5,6-dihyroindole-2-carboxylic acid (DHICA) byTRP-2, also known as dopachrome tautomerase.

Dopaquinone is converted by a series of complex reactions involvingcyclization and oxidative polymerization, which finally result in theformation of eumelanin. It was once thought that these latter reactionsoccurred spontaneously, but it now appears that certain steps are underregulatory control. For instance, there is now evidence that dopachromecan be converted to either 5,6-dihydroxyindole or the carboxy derivative5,6-dihydroxyindole carboxylic acid (DHICA). The latter step appears tobe catalyzed either by metal ions or by a recently discovered enzyme,dopachrome tautomerase, also known as TRP-2.

Dopachrome tautomerase occurs in melanosomes complexed with tyrosinaseand perhaps other melanosomal membrane proteins. In addition,peroxidases can utilize DHI as a substrate and thus may also play a rolein melanogenesis.

Another control point in the melanin biosynthetic pathway involvesTyrosine-Related Protein 1 (TRP1). Mutations in both copies of the TRP1gene lead to OcularCutaneous Albinism (OCA) type 3, resulting in partialmelanin loss. In mice and humans, TRP1 stabilizes tyrosinase and also inmice functions as DHICA oxidase.

The switch of the synthetic pathway from eumelanin to phaeomelaninrequires the presence of sulphydryl residues. Thus, if dopachromeencounters either cysteine or glutathione, cysteinyl DOPAs are formed.These are then quickly oxidized into benzothiazines and subsequently tophaeomelanins.

Regulation of Melanogenesis

The regulation of pigmentation in mammals is controlled at manydifferent levels and is quite complex at each level. Melanocytes areinitially derived from the neural crest and migrate throughout theembryo during development. These migration patterns are under strictgenetic control and can lead to some interesting patterns when the finalmelanocyte distribution in the skin is not uniform, as can be seen inzebras and giraffes. Pigmentation is also regulated at the cellularlevel by melanocytes synthesizing melanin within melanosomes, which canbe produced in varying sizes, numbers and densities. Lastly,melanogenesis is regulated at the subcellular level where the synthesisand expression of various melanogenic enzymes and inhibitors play acritical role.

Skin pigmentation depends upon the organization and functioning of theepidermal melanin unit and several separate, but related, events:

-   -   Melanoblast migration from the neural crest;    -   Melanoblast differentiation into melanocytes;    -   The rate of synthesis and melanization of melanosomes;    -   The size of melanosomes;    -   Synthesis of melanin;    -   The efficacy of melanosome transfer into keratinocytes;    -   The rate of melanosome degradation within the keratinocytes;    -   The rate of synthesis, inhibition and decay of tyrosinase;    -   Activity of tyrosinase in melanosomes

Melanocytes work in close harmony with their neighboring cells in theepidermis. They are influenced by a variety of biological factors,including interleukins, interferons, growth factors, vitamins andprostaglandins, which determine not only whether melanin is synthesized,but also what type of melanin is produced. Presumably, these factorsprovide the complex signals that stimulate pigmentation after trauma,UV-exposure, or other environmental stimuli that induce themelanocyte-stimulating hormone (MSH, or melanotropin), a peptideproduced by the posterior pituitary. Once MSH binds to melanocytesurface receptors, a dramatic, up to 100-fold, increase in melanogenesisresults.

Melanogenesis can be affected at three different time intervals (seeFIG. 2):

1. Before melanin synthesis by inhibiting transcription or glycosilationof the enzymes, thereby producing an alteration of the structure orfunction of the melanosome;

2. During melanin synthesis and when melanosomes are mature, peroxidase,ROS scavengers, reduction agents and/or lipids directly inhibittyrosinase. This would affect the uptake and distribution of melanosomesin recipient keratinocytes.

3. After melanin synthesis, melanin and melanosome degradation occurs,increasing turnover of pigmented keratynocytes. Any blockage at thislevel would inhibit melanosome transfer and dispersion of melanin.

Recent work on molecular mechanism regulating pigmentation suggests thatcAMP PKA (cyclic AMP dependent protein kinase) is the second majorintracellular signaling molecule critical for skin pigmentation. PKC B(protein kinase C beta) is a key activator of tyrosinase, acting throughphosphorylation of the protein at the cytoplasmic domain. Data suggestthat this might be the rate limiting step. Cross talk between C-AMP andPKC affects pigmentation by up-regulating the expression of PKC-B.

The cyclic AMP pathway plays an important role in the production ofmelanin and the regulation of melanogenesis. The cyclic AMP pathway inmelanocytes is activated by: ACTH, a-MSH, endothelia 1, nitrous oxide(NO) and PGE2. At the end product site, in response to UV stimulation,the keratinocytes secrete factors, such as interleukin la, interferonand TNFa. These factors inhibit melanogenesis.

Inositol Mechanism of Action

The nature of trying to lighten skin requires the use of new agents ormeans with little to no toxicity.

Inositol exists in plants as phytic acid (inositol hexaphosphate) and isalso present in avian and fish erythrocytes, where it plays a role inallosteric regulation of oxygen affinity to hemoglobin. Inositol is anessential element in many species, including humans.

Biologically, inositol is an essential component of the cell membraneand is a key component of the multiple system intracellular signalingpathways and has also been implicated in key roles in the immune system.

Inositol functions on the site-specific signals on the cell membraneactivating proteins for the assembly of spatially localized functionalcomplexes, including signal transduction, cytoskeletal and membranetrafficking events with subsequent formation of specific proteins.

Although inositol has been implicated in many different functions anduses, it has not been described or used as a lightening agent. Itseffect on pigmentation or melanogenesis has not been reported ordocumented.

We believe that inositol is a new lightening agent and works byaffecting melanogenesis, acting in the melanin pathway.

Inositol may act in the melanogenesis pathway as an inhibitor throughseveral different mechanisms. For example, it is possible that inositolacts as a transcription inhibitor by increasing the amount ofdose-dependant intra-cellular free calcium (Ca⁺⁺) in the endoplasmicreticulum, where tyrosine is glycosilated. This would result in faultyprotein production affecting the function and structure of themelanosomes.

Once melanin is glycosilated at the endoplasmic reticulum, the formedproteins are transported in vesicles to the TGN (Trans-Golgi Network)and from the TGN to the melanosomal compartment. A number of proteinshelp in the formation and transport of these vesicles includingguanosine triphosphate-binding proteins, such as rab7 and phosphatidylinositol kinase. Phosphatidyl inositol also regulates the membranetrafficking of melanosomal glycoproteins, controlling the production ofmelanin by down-regulating its substrate.

It is also possible that inositol acts as a post-transcriptionalinhibitor of melanogenic enzymes at the N-glycosilation level. Thiswould affect the protein structure of these enzymes and eventually theintracellular transport of the melanosome, reducing the level of itsexpression.

As mentioned earlier, melanogenesis results from a variety of regulatoryprocesses involving direct effects of UV radiation on the melanocyte andindirect effects through the release of its final product(down-regulation). One of the intracellular signaling pathways is cyclicAMP. This pathway plays an important role in the production of melaninand the regulation of melanogenesis. The cyclic AMP pathway inmelanocytes is activated by: ACTH, a-MSH, endothelin 1, nitrous oxide(NO) and PGE2. At the end product site, in response to the UVstimulation, the keratinocytes secrete factors, such as interleukin I a,interferon and TNFa. These factors inhibit melanogenesis. Inositolhexaphosphate increases cyclic AMP and thereby decreases the productionrate of melanin. A balance between these keratinocyte factors permitsmelanocyte growth and differentiation, ultimately controlling skinpigmentation.

BRIEF SUMMARY OF THE INVENTION

Vismia, phytic acid, arbutin, and kojic acid all have depigmentationproperties that are beneficial in dermatological applications. Phyticacid, arbutin and kojic acid act in the tyrosine metabolic pathway bydifferent mechanisms. Vismia utilizes a mechanism of action similar toan anthraquinone, where it competes with the tyrosinase substrate.Vismia, phytic acid, arbutin and kojic acid provide suitable substitutesfor hydroquinone, which has been utilized in the last decade as a skinlightening agent, but has been reported to create adverse effects inmany who use it. For this reason, the use of hydroquinone inover-the-counter formulations has been banned in Europe and Japan. Thetopical use of vismia, phytic acid, arbutin and kojic acid impacts thefinal melanin distribution in human skin.

Vismia, phytic acid, arbutin and kojic acid can be used for theprevention and/or treatment of melasma, freckles or age spots (lentigosenilis). They can also be utilized in programs designed for superficialpeeling, utilizing phytic acid in combination with arbutin and kojicacid in the concentrations proposed.

It has been explained earlier that oxidative stress damages cellularelements, which can be repaired with most known antioxidants, such asVitamin C. Unfortunately, to combat all sources of oxidative stress, itis necessary to use a large number of different antioxidants. Thepresent novel approach of the combination of vismia and phytic acidcombats free radicals that are produced during the normal process ofcellular metabolism. Phytic acid is a very potent antioxidant and isused in the industry as an anti-rust and anti-corrosion agent formetals, chelating agents for removal of metal ions, coating additive,contrast agent, developing agent, fermentation promoter, fuel anti-knockagent, gathering agent for rare earth and precious metals, highmolecular solvent, oral cleansing agent, preservative, stabilizer, watertreatment agent.

We have shown how vismia and phytic acid independently both havelightening effects on the skin. The moment vismia and phytic acid areutilized in the proposed combinations, the protection of the skin hasconsequences never seen in the history of dermatological care. Theaddition of other known skin lighteners, such as arbutin and kojic acid,provides additional benefits.

The present invention combines vismia and inositol in a novelformulation to better provide skin lightening. A brief description ofthese and several other ingredients of the formulation follows in theDetailed Description of the Invention.

The industry is in need of a non-hydroquinone lightening agent which hasno toxicity, minimal side effects and good long term effect.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. The Melanogenic pathway. Summary of the known biochemicalreactions leading to melanin synthesis from tyrosine.

FIG. 2. Possible approaches to interfere with melanogenic pathway.

FIG. 3. Photographs taken before and after one month of topicalapplication of a combination of vismia and phytic acid.

FIG. 4. Photographs taken before and after application of a controlsubstance, which contained neither vismia nor inositol.

FIG. 5. Photographs taken before, after one month and after three monthsof application of an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the claims and specification, the terms “inositol” and“phytic acid” are used interchangeably and include the salts and estersof the same.

Throughout the claims and specification, the term “topical” includes anycurrently known or future developed vehicles of administration throughhuman skin, including, but not limited to, solution, cream, lotion, gel,patch, spray, emulsion, and the like.

Throughout the claims and specification, the terms “hyperpigmentationdisorder” and “hyperpigmented disorder” are used interchangeably torefer to melasma, postinflamatory hyperpigmentation, irregularpigmentation secondary to photodamage, lentigenes (age-spots), and druginduced hyperpigmentation.

The present invention utilizes a combination of vismia and inositol totreat hyperpigmentation disorders such as melasma, postinflamatoryhyperpigmentation, irregular pigmentation secondary to photodamage,lentigenes (age-spots) and others. Additional ingredients, such asarbutin, kojic acid, antioxidants, and quinones may be included informulations of the present invention. The formulations of the presentinvention may take any known topical forms, including, but not limitedto creams, ointments, gels and the like. Some information on theindividual ingredients is presented below:

A. Vismia

Vismia spp. are trees or tall shrubs growing primarily in the tropicaland subtropical regions of South and Central America, with a few speciesalso found in Africa and Asia. Of the roughly fifty Vismia spp known,fifteen are found in Venezuela. The latex from Vismia anhusta is used bymany Indian tribes of the Colombian Amazonia to treat wounds andinfected sores and is used by the Tikunas to treat fungus and herpes. Atea from Vismia confertiflora is used by the Yakunas and Makunas of theMiritiparana and Popeyaka Rivers as a diuretic. The same tribe of theMakunas use an exudate of Vismia Tomentosa for skin dermatitis. Theorange “latex” from Vismia dealbata is used by the Puinaves to treatskin diseases (maladies) from fungal origin. The resin from VismiaFerruginea is applied to wounds in the Colombian, Brazilian and PeruvianAmazonia. A mixture of leaves of Vismia Guineensis and CanthiumGlabriflorum is used as a blood tonic for children in the PejehunDistrict of Sierra Leone, West Africa. Vismia micrantha has been used asa purgative, tonic, febrifuge and antireumathic agent. Vismia latifoliaChoisy is well known in the Brazilian and Colombian Amazonia for its useas a febrifuge. An exudate of Vismia tomentosa is used by the Mikunatribe to treat red skin rashes. The resin extracted from the tree ofVismia angusta is used for sores, skin infections, and for the treatmentof ringworm or “caracha” (a fungal dermatosis). Amazonian Colombians usethe latex for infected sores and wounds. Vismiaphenone D isolated fromextracts of leaves of Vismia Cayennensis, has HIV-inhibitory activity inthe NCI primary screen. The pounded yellowish-red resin from VismiaGuineensis makes an ointment for craw-craw; the sap is reportedlyapplied to circumcision wounds in Sierra Leone.

Vismin was isolated from Vismia macrophyla. No prior study has describedthe use of Vismia and its compounds or the activity of its extracts, noris there any suggestion that anthracenone compounds, such as vismin, areuseful as hypopigmentation agents. Among the sixty known species, morethan fifteen species of Vismia have been investigated; the chemistry ofthe Guttiferae family has been widely studied. Several species from thisgenus have been shown to contain anthranoids and xanthones.Anthraquinones, Vismiaquinone C and Vismiaquinone (Benzophenones) havebeen identified as chemical constituents of Vismia parviflora.Vismiaquinones have also been isolated from Vismia Latifolia, whose usein the Brazilian and Colombian Amazonia for dermatological purposes isquite popular.

The compositions of the present invention yield optimal results withbetween one (1) and five (5) percent by weight vismia and/or itsderviates, based on the weight of the total composition.

B. Inositol

Inositol, as a hexadroxy alcohol, is present in plasma membranes and isthe source of second messengers that are involved in the action of somehormones throughout the body controlling the secretion of hormones suchas gonadotropes and testosterone.

Inositol hexaphosphate has a demonstrably anti-cancer action against avariety of tumors.

Phytic acid, also known as inositolhexaphosphoric acid and found ingrains, can reduce calcium absorption. Large quantities of refinedsugar, caffeine and soda drinks can increase calcium excretion. Phyticacid acts as a chelating agent due to its six reactive phosphate groups.It is a complex agent for removal of traces of heavy metal ions, actingalso as a hypocalcemic agent. For its properties as a chelating agentfor calcium and for augmenting and hardening the dentist cement, phyticacid is employed in dentistry including dental creams and chewing gums.Phytic acid also modulates the release of insulin from pancreatic cellsby inhibiting serine/threonine proteins on calcium channels.

In vivo studies have shown the anticarcinogenic effects of phytic acidon skin cancer. Laboratory studies of phytochemicals, such as phyticacid, have demonstrated potentially important anticarcinogenicproperties having an important chemoprotective role.

High-fiber diets are beneficial for its effects on preventingtumorigenesis. Phytic acid is a fiber-associated component of cerealsand legumes and has been demonstrated to inhibit cell proliferation andenhance cell differentiation, indicating its chemoprotective role.

Wheat bran and its component, phytic acid, decreases coloncarcinogenesis.

Phytic acid has an important role as a growth factor, reproduced inanimal models.

Phytic acid is a physiological antioxidant with potential to formcomplexes with cations linked to cell proliferation andhypercholesterolemia. Antioxidants are produced by the skin to protectit against free radical attacks. Phytic acid is a specific antioxidantof reactive oxygen.

Phytic acid acts as a chelating agent due to its six reactive phosphategroups, it is a complex agent for removal of traces of heavy metal ions,acting also as a hypocalcemic agent.

It is known that phytic acid is a vital component of the cell membrane,where it constitutes a sea of lipids in a fluid state, in which lipidsand proteins are able to move and interact. Phytic acid is depleted inphotodamaged skin. It is reasonable to replace this deficiency in aconvenient manner by incorporating phytic acid into moisturizers anddermatological products used by patients.

Phytic acid has great benefits correcting hyperpigmentation disorderssuch as melasma and post inflammatory hyperpigmentation. Because of itsanti-inflammatory characteristics, phytic acid prevents postinflammatory lesions in the inflammatory phase of skin peeling at thethird and fourth weeks, reducing tremendously the inflammatory processand consequently diminishing the chance of formation of hyperchromicmarks from these peelings.

The compositions of the present invention yield optimal results withbetween one (1) and five (5) percent by weight inositol and/or itsderviates, based on the weight of the total composition.

As discussed earlier, topical application of the combination of inositoland vismia provides unexpected results in the treatment ofhyperpigmentation disorders such as melasma, postinflamatoryhyperpigmentation, irregular pigmentation secondary to photodamage,lentigenes (age-spots) and others. The following ingredients provideadditional benefits to compositions of the present invention.

C. Arbutin

Arbutin has been used in traditional medicine for cystitis as an urinarydisinfectant and has been especially effective with alkaline urinecaused by vegetarian diet. Arbutin alone has been reported to be aneffective urinary antibiotic, but only if taken in large doses and ifthe urine is alkaline (once again documenting the value of whole plantmedicines). It is reported to be active against Candida albicans and S.aureus, and especially active against E. coli. Uva ursi also hasdiuretic properties. Arbutin is hydrolyzed to hydroquinone and glucosein the body. Hydroquinone is most effective in an alkaline urine;however, crude plant extracts are more effective medicinally thanisolated Arbutin. This appears to be related to the activity of gallicacid, which prevents the splitting of Arbutin by such enzymes asbeta-glucosidase. Uva Ursi reported to be especially active againstE.Coli, also has diuretic effects. Arbutin is a medication withdepigmentation properties. Arbutin inhibits tyrosinase, inhibitingmelanin synthesis acting as a depigmentator. Arbutin inhibits tyrosinaseactivity in a synergistic manner by acting through a different actionmechanism. Arbutin similarly inhibits enzyme activity of human- andmushroom-tyrosinases. Arbutin inhibits melanin production by competitiveinhibition of tyrosinase activity. Arbutin is found in bearberry(Arctostaphylos uva-urs). It is extracted from the leaves of the plant,where arbutin is about 8% of the leaves, and methyl arbutin, flavinoids,phenolic acids, volatile oils and resins are the rest. Uva ursi is asmall evergreen shrub found in the northern United States and in Europe.A single long, fibrous main root sends out several prostate or buriedstems 4-6 inches high. The bark is dark brown, the leaves are obovate tospatulate and 0.5-1 inch long. The flowers are pink or white, growing insparse terminal clusters. The fruit is a bright red or pink. This planthas a long history of use for its diuretic and astringent properties.Conditions for which it has been used include chronic cystitis,nephritis, kidney stones, and bronchitis.

Some early animal research is now showing that arbutin, and possiblyother constituents of uva ursi, potentiate the activity of commonlyprescribed anti-inflammatory drugs. One study found that an aqueousextract increased the inhibitory activity of dexamethasone in allergicand inflammatory models, without increasing any of the side effects.Similar results have been demonstrated with isolated arbutin whencombined with indomethacin. Crude extracts are widely used in Europe ascomponents in certain diuretic and laxative products.

The compositions of the present invention yield optimal results withbetween two (2) and four (4) percent by weight arbutin and/or itsderviates, based on the weight of the total composition.

D. Kojic Acid

Kojic acid, like arbutin and phytic acid, has depigmentation properties.All three compounds have the same mechanism of action, acting in thetyrosine metabolic pathway, inhibiting tyrosinase. Kojic acid is afungal metabolite produced by Aspergillus and Penicillium spp. It isstructurally related to maltol. Like maltol, it is a good chelator oftransition metal ions and has been shown to inhibit tyrosinase activity.Kojic acid was shown to inhibit tyrosinase isolated from black goldfishand standard goldfish and to suppress melanogenesis in cultured pigmentcells. When kojic acid was ingested by the fish, the black goldfishbecame almost yellow-brown. Kojic acid improves hyperpigmentationdisorders including facial melasma, freckles (lentigo aestiva) or agespots (lentigo senilis). It has been shown that kojic acid peels areless drying to skin than glycolic or salycilic acid.

The compositions of the present invention yield optimal results withbetween two (2) and four (4) percent by weight kojic acid and/or itsderviates, based on the weight of the total composition.

E. Antioxidants

Antioxidants are scavengers of highly reactive oxygen species, theso-called free radicals, which are capable of degrading lipidconstituents of cell membranes, proteins and DNA.

Vitamin C and Vitamin E and, to a lesser extent, Vitamin A, are wellknown free radical scavengers. Superoxide dismutase is a natural proteinwith endogenous antioxidant properties.

Antioxidants play an important role in skin cosmetics. The skin is avery sensitive organ to all forms of harmful effects. More than anyother tissue in the body, it is exposed to different changes intemperature and different types of radiation, which not only harm theskin but also induce the formation of free radicals, which reduce thenatural antioxidants in the skin.

In normal conditions the cells of the body have antioxidant pools.Several types of antioxidants combat the production of free radicalsphysiologically.

Any lack of this equilibrium retains the production in the activity ofthis oxidant pool, determining an alteration of the cellularhomeostasis, which is called oxidative stress. The oxidative stresscauses deficiency of antioxidant molecules and also increases in theoxidants (free radicals). The consequences are irreversible destructionof the cellular membrane, nucleus, nucleic acids, DNA and RNA oxidationof other proteins and cellular enzymes. The hydroxyl radicals areespecially set to begin the lipid perioxidation in the cell membraneforming secondary products. These secondary products are involved in theorganic aging both internal and external in the carcinogens.

The oxidative stress is more important in several dermal diseases: heatinduced lesions, ionized infrared radiation, psoriasis, photodermatosis,seborrheic dermatitis. The oxidative stress is equally implicated in aprocess that affects all of us: Both intrinsic and extrinsic aging.

The search for substances that decreases the process of aging of skinand other cells of the human body involves the knowledge of severalsubstances that can act as destructor of those free radicals. Theantioxidants can be used in this topical area or systemic. Vegetablesreceive both UVA and UVB radiations and constantly develop sophisticatedmethods to minimize the oxygen radicals (free radicals). There are manyantioxidants in the grain, leaves or fruits, the wax around the leaves,the oil producing bean and herbs. It is interesting to note that thelevels of antioxidants vary in the vegetables according of the season ofthe year. The prevention of oxidation in the sophisticated foodspromotes the preservation of the food.

Other antioxidants that are encountered in vegetables includeantioxidants of the tanino (present in the guadana-fruit and leaves).These antioxidants are encountered in the chips of eucalyptus andglucoside antioxidants of the wood encountered in the seeds of gerdalin.The research that has been going on about antioxidants are centered inthe gathering analysis of materials from plants that exist in naturesuch as the compounds present in this invention. Phytic acid acts notonly as an antioxidant but as an antiinflamatory agent, having hydratingproperties which means that it can be used as a skin cleanser with adegree of sensibility like white skin and sensitive skin or skin thathave suffered great aggressions by any other chemical or physicalprocess.

Quinones

Anthraquinone is the most important quinine derivative of anthracene andquinine, and the parent substance of a large class of dyes and pigments.It is used in paper industry as a catalyst to increase pulp production.Sixteen new prenylated anthraquinones and xanthones have been isolatedfrom Vismia guineensis.

Anthraquinone is also found in different plants such as Aloe Vera. Thebitter juice contains anthraquinone glycosides and free anthraquinonesresins. It as been used in burns, cuts and wounds. Anthraquinone is alsoknown to bind free radicals resulting in antioxidant properties.

The reduction of quinone to the corresponding dihydroxy form is animportant characteristic reaction that yields Hydroquinone that is usedin dermatology as an antioxidant, inhibiting polymerization by directreaction with peroxy-free radicals.

Quinones are also used as agents for skin lightening. Hydroquinone hasbeen the standard dermatological depigmentation agent for the last fortyyears. Hydroquinone inhibits the tyrosinase enzyme. Although it is thecurrent standard dermatological depigmenting agent, hydroquinone iscytotoxic in that it destroys the cellular walls of the melanocytes.Prolonged use of hydroquinone can also produce Ochronosis, a conditionthat gives skin a bluish/gray pigmentation, which is permanent in somecases. When topical compositions containing two percent or more ofhydroquinone are used for more than sixty days, irreversible lesions mayform, such as confetti lesions or residual acromia.

G. Formulations

The nature of trying to lighten skin requires the use of new agents ormeans with little to no toxicity. As discussed above, prolonged use ofhydroquinone to lighten skin can result in irreversible damage. Vismia,phytic acid, arbutin and kojic acid provide a suitable substitute forhydroquinone. While arbutin and kojic acid are both documenteddepigmentation agents, neither agent alone provides the benefitsachieved by the combination of vismia and phytic acid. Half face studiesare currently in trial comparing the industry standard, hydroquinone,with compositions of the present invention. The expected result is anovel and non-toxic treatment of hyperpigmentation disorders such asmelasma, postinflamatory hyperpigmentation, irregular pigmentationsecondary to photodamage, lentigenes (age-spots) and others.

The invention will now be further described with reference to thefollowing examples and figures, which are provided for illustrative andnon-limiting purposes:

EXAMPLE 1 Skin Brightener Formula (One Embodiment of Present Invention)

Ingredients % (w/w) Alpha/Arbutin 1 Ascorbic Acid 1 Cetearyl Alcohol 3Citric Acid 2 Fragrance 0.2 Green Tea Extract 1 Water 63 IsopropylPalmitate 5 Inositol Hexanicotinate 4 Kojic Acid Dipalmitate 2 MenthylLactate 1 Arachidyl Alcohol, Behenyl Alcohol and Arachidylglucoside 0.3Preservative 5 Hyaluronic acid/Sodium Lactate 0.3 Propylene Glycol 3Rumex Crispus Extract 3 Polyacrylamide & C13-14 isoparaffin andlaureth-7 3 Vismia 2 Vitamin E 0.2

EXAMPLE 2 Skin Brightener Formula (Another Embodiment of PresentInvention)

Ingredients % (w/w) Alpha/Arbutin 1 Ascorbic Acid 1 Cetearyl Alcohol 3Citric Acid 2 Fragrance 0.2 Green Tea Extract 1 Water 67 IsopropylPalmitate 5 Inositol Hexanicotinate 1 Kojic Acid Dipalmitate 1 MenthylLactate 0.4 Arachidyl Alcohol, Behenyl Alcohol and Arachidylglucoside 5Preservative 0.3 Hyaluronic acid/Sodium Lactate 3 Propylene Glycol 3Rumex Crispus Extract 3 Polyacrylamide & C13-14 isoparaffin andlaureth-7 2 Vismia 1 Vitamin E 0.1

EXAMPLE 3 Skin Brightener Formula (Another Embodiment of PresentInvention)

Ingredients % (w/w) Ascorbic Acid 1 Cetearyl Alcohol 3 Citric Acid 2Fragrance 0.2 Green Tea Extract 1 Water 63 Isopropyl Palmitate 5Inositol Hexanicotinate 5 Menthyl Lactate 1 Arachidyl Alcohol, BehenylAlcohol and Arachidylglucoside 0.3 Preservative 5 Hyaluronic acid/SodiumLactate 0.3 Propylene Glycol 3 Rumex Crispus Extract 3 Polyacrylamide &C13-14 isoparaffin and laureth-7 3 Vismia 4 Vitamin E 0.2

EXAMPLE 4 Skin Brightener Formula (No Vismia)

Ingredients % (w/w) Alpha/Arbutin 2 Ascorbic Acid 2 Cetearyl Alcohol 3Citric Acid 2 Fragrance 0.2 Green Tea Extract 1 Water 64 IsopropylPalmitate 5 Inositol Hexanicotinate 3 Kojic Acid Dipalmitate 2 MenthylLactate 1 Arachidyl Alcohol, Behenyl Alcohol and Arachidylglucoside 0.3Preservative 5 Hyaluronic acid/Sodium Lactate 0.3 Propylene Glycol 3Rumex Crispus Extract 3 Polyacrylamide & C13-14 isoparaffin andlaureth-7 3 Vitamin E 0.2

EXAMPLE 5 Skin Brightener Formula (Control—No Vismia, No Inositol)

Ingredients % (w/w) Alpha/Arbutin 2 Ascorbic Acid 2 Cetearyl Alcohol 3Citric Acid 2 Fragrance 0.2 Green Tea Extract 1 Water 66 IsopropylPalmitate 5 Kojic Acid Dipalmitate 3 Menthyl Lactate 1 ArachidylAlcohol, Behenyl Alcohol and Arachidylglucoside 0.3 Preservative 5Hyaluronic acid/Sodium Lactate 0.3 Propylene Glycol 3 Rumex CrispusExtract 3 Polyacrylamide & C13-14 isoparaffin and laureth-7 3 Vitamin E0.2

EXAMPLE 6 Skin Brightener Formula (Control—No Skin Lighteners)

Ingredients % (w/w) Ascorbic Acid 2 Cetearyl Alcohol 3 Citric Acid 2Fragrance 0.2 Green Tea Extract 1 Water 71 Isopropyl Palmitate 5 MenthylLactate 1 Arachidyl Alcohol, Behenyl Alcohol and Arachidylglucoside 0.3Preservative 5 Hyaluronic acid/Sodium Lactate 0.3 Propylene Glycol 3Rumex Crispus Extract 3 Polyacrylamide & C13-14 isoparaffin andlaureth-7 3 Vitamin E 0.2

As indicated by Examples 1 through 3, several formulations containingvarying amounts of vismia and phytic acid have been produced and testedand have yielded amazing results. In FIG. 3, a patient is shown beforeand after one month of topical application of one embodiment of thepresent invention containing a combination of vismia and phytic acid.FIG. 4 provides a control study wherein a patient was provided with aformulation containing neither vismia nor phytic, similar to Example 6,and no improvements were demonstrated. FIG. 5 demonstrates theimprovements yielded by three months of application of one embodiment ofthe present invention. Applicants have tested many differentcombinations and formulations containing vismia, phytic acid, arbutin,kojic acid and hydroquinone. None of these combinations have surpassedthe results exhibited by the formulations containing both vismia andphytic acid.

The Examples and Figures have been provided for exemplary purpose only.It is to be understood that the invention is not limited to theembodiments disclosed in the Examples and Figures, but is intended tocover various modifications and equivalent arrangements included withinthe spirit of the invention, which are set forth in the appended claims,and which scope is to be accorded the broadest interpretation so as toencompass all such modifications and equivalent structures.

1. A topical composition comprising a mixture of vismia extract in anamount effective to lighten skin and phytic acid in an amount effectiveto lighten skin.
 2. The topical composition of claim 1 wherein saidamount of vismia extract effective to lighten skin comprises from aboutone to about five percent as a percent weight of said composition. 3.The topical composition of claim 2 wherein said amount of phytic acideffective to lighten skin comprises from about one to about five percentas a percent weight of said composition.
 4. The topical composition ofclaim 1 wherein said composition treats hyperpigmentation disorders. 5.The topical composition of claim 1 further comprising arbutin.
 6. Thetopical composition of claim 2 further comprising arbutin.
 7. Thetopical composition of claim 3 further comprising arbutin.
 8. Thetopical composition of claim 1 further comprising kojic acid.
 9. Thetopical composition of claim 2 further comprising kojic acid.
 10. Thetopical composition of claim 3 further comprising kojic acid.
 11. Atopical composition comprising: about one to about five percent vismiaextract, wherein about one to about five percent is an amount of vismiaextract effective to lighten skin; and about one to about five percentphytic acid, wherein about one to about five percent is an amount ofphytic acid effective to lighten skin.
 12. The topical composition ofclaim 11 wherein said composition treats hyperpigmentation disorders.14. The topical composition of claim 11 further comprising arbutin. 15.The topical composition of claim 11 further comprising kojic acid.
 16. Atopical composition comprising. about one to about five percent vismiaextract, wherein about one to about five percent is an amount of vismiaextract effective for lightening skin; about one to about five percentphytic acid, wherein about one to about five percent is an amount ofphytic acid effective for lightening skin; and arbutin.
 17. A topicalcomposition comprising. about one to about five percent vismia extract,wherein about one to about five percent is an amount of vismia extracteffective for lightening skin; about one to about five percent phyticacid, wherein about one to about five percent is an amount of phyticacid effective for lightening skin; and kojic acid.